Allelic loss and loss of function of tumor suppressor genes (TSGs) are the most frequent genetic abnormalities in lung cancer. Replacement of TSG function alone is therapeutic and often leads to lung cancer cells undergoing apoptosis or cell cycle arrest in vitro. Currently it appears that such replacement therapy must be done with genes rather than small-molecule mimics of TSGs. We recently demonstrated that restoration of function of 3p21.3 TSG FUS1, a proapoptotic protein, with the use of systemic nanoparticle delivery successfully cured mice with large human lung cancer orthotopic xenografts. In a phase I clinical trial systemic nanoparticle therapy delivered the FUS1 TSG to distant sites in stage IV nonsmall cell lung cancer (NSCLC) patients after intravenous injection. The FUS1 gene is inactivated in primary tumors due to 3p21.3 allele haploinsufficiency and defective post-translational modification of the remaining gene product. Enforced expression of the wild-type FUS1 in 3p21.3-deficient NSCLC cells significantly suppressed tumor cell growth by induction of apoptosis, functioning as a TSG in vitro and in vivo. However, FUS1 overexpression in human bronchial epithelial cells and other normal cells does not affect their viability. We also observed that exogenous expression of wild-type FUS1 protein in NSCLC and SCLC cells deficient in FUS1 had inhibitory effects on several oncogenic protein tyrosine kinases (PTKs), including EGFR, PDGFR, c-abl, and c-kit in NSCLC and small cell lung cancer cell lines. Associated with this PTK inhibition, there was a markedly enhanced cell response to the clinically available tyrosine kinase inhibitors (TKIs) imatinib and gefitinib. Thus, combined treatment with FUS1 and TKIs led to a significant growth inhibitory effect on lung cancer cells that were resistant to TKIs given alone. We hypothesize that treatment with the FUS1 gene delivered by nanoparticles combined with TKI therapy will have additive or supra-additive growth inhibitory and pro-apoptotic effects on lung cancer cells overcoming TKI-induced or intrinsic resistance. Our long-term goal is to develop personalized, pathway-targeted treatments which are more effective and less toxic than current treatments. The specific aims in this proposed study are 1) to determine whether FUS1-induced apoptosis and growth arrest are potentiated in various lung cancer cells /n vitro and in vivo in tumor xenograft models by TKIs that are currently being used in the clinic, 2) to identify sensitivity and resistance phenotypes associated with FUS1 expression and molecular signatures associated with these phenotypes in human lung cancer cell lines and tumor specimens and validate candidate signature molecules in a larger population of lung cancer cell lines, tumor xenografts, and clinical specimens from lung cancer patients, and 3) to conduct a Phase l/ll clinical trial combining Fl/S7-nanoparticles and erlotinib in stage IV lung cancer patients who have progressed following treatment with platinum-containing regimens.